Mutations in RAS or the kinase BRAF promote the growth of various cancers, most notably melanoma. However, these oncogenic mutants also induce a state of stable cell cycle arrest called cellular senescence in premalignant cells, such as those in melanocytic nevi (commonly called moles), thereby limiting their expansion. Oncogenic RAS/BRAF-induced senescence is mediated by the methylation of promoters of cell proliferation–associated genes; however, some cells eventually overcome senescence to generate melanomas. Identifying the early and critical mechanisms of the nevus-to-melanoma switch will enable clinicians to more effectively diagnose malignant growths earlier and monitor at-risk patients. Yu et al. found that escape from senescence in melanocytic nevi is critically mediated by the expression of two histone demethylases, LSD1 and JMJD2C. Increased amounts of LSD1 or JMJD2C, as are seen in a subset of melanoma patient samples and cell lines, not only correlated with demethylation of those gene promoters and encouraged cell cycle reentry and proliferation of cells expressing RAS/BRAF mutants but also promoted the growth of more aggressive tumors that metastasized in mice. Knockdown or pharmacological inhibition of LSD1 or JMJD2 family members induced proliferating melanoma cells to reenter senescence in culture and in mouse models. Both demethylases are overexpressed in other tumor types as well. These findings exemplify the central role of epigenetics in regulating cell cycle signaling and cancer development and, hence, further strengthen the prospect of targeting epigenetic modifiers for cancer therapy (see also Wagner and Gil).